Triple negative (ER-negative, PR-negative/unknown, HER2-negative) advanced or metastatic breast cancer
Conditions
Interventions
Product Name: AZD5363
Product Code: AZD5363
Pharmaceutical Form: Tablet
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 80-200
Pharmaceutical form of the placebo: T
Sponsors
Queen Mary University of London
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Each patient must meet all of the following inclusion criteria to be enrolled in the study: 1. Written informed consent prior to admission to this study 2. Women, age = 18 years 3. Histologically confirmed breast cancer 4. Metastatic or locally recurrent disease; locally recurrent disease must not be amenable to resection with curative intent (patients who are considered suitable for surgical or ablative techniques following potential down-staging with study treatment are not eligible). 5. Patients must have • at least one lesion, not previously irradiated, that can be measured accurately at baseline as =10 mm in the longest diameter (except lymph nodes which must have short axis =15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements, or • lytic or mixed (lytic + sclerotic) bone lesions in the absence of measurable disease as defined above; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible 6. Radiological or clinical evidence of recurrence or progression 7. Triple-negative disease, defined as tumour cells being • negative for ER with =65 years) yes F.1.3.1 Number of subjects for this age range 30
Exclusion criteria
Exclusion criteria: Patients meeting any of the following exclusion criteria are not to be enrolled in the study. 1. Patients with confirmed brain metastases or a history of primary central nervous system tumors or who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases. Patients with treated brain metastases that are asymptomatic and have been clinically stable for 3 months will be eligible for protocol participation 2. Prior chemotherapy for metastatic breast cancer 3. Radiotherapy with a wide field of radiation (greater than or equal to 30% marrow or whole pelvis or spine) within 4 weeks before the first dose of study medication (AZD5363/placebo) 4. Prior treatment with PI3K inhibitors, AKT inhibitors or mTOR inhibitors. 5. Prior treatment with paclitaxel or docetaxel in the (neo)adjuvant setting within 12 months from the end of paclitaxel or docetaxel treatment and inclusion into this study 6. Preexisting sensory or motor polyneuropathy = Grade 2 according to NCI CTC 7. Malabsorption syndrome or other condition that would interfere with enteral absorption 8. Clinically significant pulmonary dysfunction 9. QTc Prolongation defined as a QTc interval >470 msecs or other significant abnormalities in rhythm, conduction or morphology of resting ECG including 2nd degree (type II) or 3rd degree AV block or bradycardia (ventricular rate 500mg/24 hours) or creatinine > 1.5 x ULN concurrent with creatinine clearance <50 mL/min 14. Exposure to potent inhibitors or inducers or substrates of CYP3A4 or substrates of CYP2D6 within 2 weeks before the first dose of study treatment (3 weeks for St John’s Wort) (for details please refer to Appendix 2). 15. Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days prior to study entry. 16. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining inf
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The main aim of this study in all treated patients and in patients with and without aberrant activation of the PI3K/AKT pathway is: Progression-free survival, defined as the time from the date of randomisation to the date of first documented tumour progression (using RECIST1.1) or death from any cause, whichever occurs first.;Secondary Objective: The secondary aims of the study in all treated patients and in patients with and without aberrant activation of the PI3K/AKT pathway are: • Objective response, defined as a complete or partial response (as assessed by the site radiologist and/or investigator, using RECIST 1.1) • Average change (%) in tumour size at 8 weeks compared to baseline, as assessed by RECIST 1.1); tumour size is defined as the sum of the longest diameters of the target (i.e. measurable tumour) lesions • Clinical Benefit (CB), defined as number of patients with complete or partial response or stable disease maintained =24 weeks (as assessed by the site radiologist and/or investigator, using RECIST 1.1). • Overall survival, defined as the time from date of randomisation to the date of death due to any cause • Duration of response, defined as the time from first documentation of complete or partial response to disease progression (as assessed by the site radiologist and/or investigator, using RECIST 1.1) •;Primary end point(s): The primary outcome measure for this study is progression-free survival. ;Timepoint(s) of evaluation of this end point: Progression free survival is defined as the time from the date of randomisation to the date of first documented tumour progression based on investigator assessment (using RECIST 1.1) or death from any cause, whichever occurs first. Tumour assessments of progression will be performed at screening, weeks 8, 16 and 24, and every 12 weeks thereafter, at the end of treatment and at follow-up. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Efficacy The secondary outcome measures in all treated patients and in patients with and without aberrant activation of the PI3K/AKT pathway are: 1. Objective response, defined as a complete or partial response (as assessed by the site radiologist and/or investigator, using RECIST 1.1) 2. Average change (%) in tumour size at 8 weeks compared to baseline, as assessed by RECIST 1.1); tumour size is defined as the sum of the longest diameters of the target (i.e. measurable tumour) lesions 3. Clinical Benefit (CB), defined as number of patients with complete or partial response or stable disease maintained =24 weeks (as assessed by the site radiologist and/or investigator, using RECIST 1.1). 4. Overall survival, defined as the time from date of randomisation to the date of death due to any cause 5. Duration of response, defined as the time from first documentation of complete or partial response to disease progression (as assessed by the site radiologist and/or investigator, using RECIST 1.1) 6. Duration of clinical benefit, defined as the time from randomisation to disease progression (as assessed by the site radiologist and/or investigator, using RECIST1.1) in patients with CB 7. 8-week progression-free survival and 24-week progression-free survival, respectively, defined as the percentage of patients with an 8 or 24 week visit response of CR, PR or SD (as defined by RECIST 1.1) with no evidence of previous progression. 8. Patient reported outcomes, as assessed by the Functional Assessment of Cancer Therapy-General (FACT-G) scale, the Functional Assessment of Cancer Therapy-Diarrhoea (FACT-D) subscale, the Functional Assessment of Cancer Therapy – EGFRI (FACT-EGFRI) subscale, and the Euro-QOL 5D (EQ-5D) Safety Outcome Measures The safety outcome measures for this study are as follows: • Incidence of serious adverse events • Incidence of grade 3 and 4 adverse events (CTCAE, version 4.03) • Incidence of all adverse events of all grades • Inc | — |
Countries
France, Georgia, Hungary, Korea, Republic of, Romania, United Kingdom
Contacts
Public ContactPAKT Trial Coordinator
Centre for Experimental Cancer Medicine, Barts Cancer Institute
Outcome results
None listed